The specific aim of this project is to gain a better understanding of the structural features necessary for agonist and antagonist activity at Alpha-adrenergic receptors. The proposed work is centered around the use of imidazoline derivatives as molecules to probe the stereochemical requirement for Alpha-adrenergic receptors. Recently, Alpha-adrenergic receptors have been subclassified and to date, little data is available which attempts to characterize and to optimize the interaction of imidazoline drugs with Alpha-adrenergic receptors. Our specific aims are (1) to synthesize, isolate, and characterize a series of imidazoline analogs, (2) in those instances where it is appropriate, we plan to resolve the analogs into the respective optical isomers for biological studies, (3) to carry out pharmacological studies on the imidazoline derivatives on selected tissues in order to note any significant differences on the Alpha-adrenergic receptor subtypes (Alpha1- and Alpha2-adrenergic receptors), (4) to examine the imidazoline optical isomers on Alpha-adrenergic receptors and to see what the relationship is to the classical Easson-Stedman Theory for catecholamines, (5) to determine for those molecules possessing significant Alpha-adrenergic activity a profile of pharmacological activity in the central and peripheral nervous system including actions on Beta-adrenergic (Beta1 and Beta2), histimine (H1 and H2) and dopamine receptors, and (6) to carry out radiolabeled ligand binding displacement studies with selected imidazoline derivatives in order to correlate pharmacological activity to the binding studies. The studies proposed should provide new insights into what effect substitutions have on known imidazoline agonist and antagonist and provide new findings as to the stereochemical requirements for adrenoceptors (Alpha1-, Alpha2-, and Beta1-, Beta2-). Drugs that could result from a better understanding of the structural requirements for the subtypes of Alpha-receptors could result in a more selective means of treating nasal congestion, hypertension, hypotention, and cardiac disorders.